Predictors of therapeutic benefit from amitriptyline in mild depression: a general practice placebo-controlled trial

Journal of Affecttve Disorders, 14 (1988) 83-95 Elsevier

83

JAD 00520

Predictors of therapeutic benefit from amitriptyline in mild depression: a general practice placebo-controlled trial E.S. Paykel, J.A. Hollyman,

P. Freeling

and P. Sedgwick

University of Cambridge and St. George’s Hospital Medical School, London, U.K. (Accepted

5 October

1987)

Summary General practice depressives were treated for 6 weeks with amitriptyline or placebo in a controlled trial. Overall, drug was found strongly superior to placebo. Interactions were examined between drug effects and a number of variables, principally reflecting demographic characteristics, history of illness, severity of illness, and endogenous depression separately in symptoms and stress. Only in the area of severity were significant interactions found. Amitriptyline was superior to placebo in probable or definite major depression on the Research Diagnostic Criteria, but not in minor depression. It was also superior to placebo in subjects with initial scores on the Hamilton Depression Scale of 13-15, and 16 or more, but not with lower scores. Findings indicate that tricyclic antidepressants are of considerable benefit in relatively mild depressions, except in the mildest range.

Key words: Amitriptyline;

Mild depression;

Therapeutic

Introduction The majority of depressed patients in the United Kingdom are treated in general practice. Available figures suggest that only between one-sixth and one-tenth are referred to psychiatrists (Sireling et al., 1985a). Even in the U.S.A., where primary care is less well developed and specialist care more so, about half the patients with milder disorders in the community receiving care do so from general medical rather than specialist mental health pro-

Address for correspondence: Professor ES. Paykel, Department of Psychiatry, University of Cambridge. Addenbrooke’s Hospital, Cambridge CB2 2QQ, U.K. 0165-0327/88/$03.50

6 1988 Elsevier Science Publishers

benefit

viders (Schurman et al., 1985). The majority of prescribing of tricyclic antidepressants is also in general practice. In 1985 more than 7.3 million prescriptions were filled by retail pharmacies in Great Britain for antidepressants, mainly tricyclics (personal correspondence, DHSS). There is much evidence as to efficacy of tricyclic antidepressants and the types of patients who respond (Paykel, 1979). However, almost all of it depends on depressives of moderate or greater severity, treated by psychiatrists. There have been few placebo-controlled trials in general practice to establish effectiveness and which types of patient may show benefit by superiority of drug over placebo. In Britain, Porter (1970) found imipra-

B.V. (Biomedical

Division)

84 mine 75-150 rng no better than placebo in a 3-week study, but Thomson et al. (1982) found amitriptyline clearly superior to placebo. In Australia Blashki et al. (1971) found amitriptyline 150 mg daily, but not 75 mg daily, superior to placebo and in the U.S.A. Rickels et al. (1970) have found antidepressants effective in several studies. Because conditions of general practice differ between countries different kinds of patients may have been treated in these studies. Although these studies do indicate that antidepressants are of value, they give little clue as to the types of patients who benefit, since most have not reported any analyses within subgroups. Nor is it clear that criteria and referral procedures have not selected patients unrepresentative of the usual general practice depressives. Some selection procedures inevitably tend to bias therapeutic trial samples. A number of studies (Fahy, 1974; Johnson and Mellor, 1977), including one of our own (Sireling et al., 1985a,b), have indicated that general practice depressives as a whole have milder, shorter illnesses than psychiatric samples, with depression less endogenous in symptom pattern and more related to recent situational stress. There is a copious literature on factors relating to therapeutic response to tricyclic antidepressants (Bielski and Friedel, 1976; Paykel, 1979). However, relatively little attention has been given to the milder end of the spectrum and to the distinction, very important in establishing guidelines for treatment in clinical practice, between those depressions which benefit from antidepressants and those which either because of good spontaneous outcome or because of poor drug effect fail to show drug-placebo differences, indicating that drug treatment would be inappropriate. We have elsewhere reported (Hollyman et al., in press) overall findings for the whole sample from a relatively large placebo-controlled trial of amitriptyline in general practice depression. Strong antidepressant effects were demonstrated. We here report detailed analyses aimed at isolating responsive and non-responsive subgroups. Methods Subjects Subjects were 141 patients aged 18-64 inclusive with depression, attending their general practi-

tioner, regarded by him as requiring antidepressant treatment and not requiring referral to a psychiatrist. They were under the care of 41 general practitioners in South West London and adjacent areas of Surrey. For inclusion, patients were required to satisfy the Research Diagnostic Criteria (RDC) (Spitzer et al., 1978) for probable or definite major, minor or intermittent depression. There was a minimum duration of illness of 1 week, and a minimum total score of 6 and a maximum of 27 on the 17-item Hamilton Depression Scale (Hamilton, 1967). In fact few patients were excluded on these criteria; the actual maximum initial score of any completing patient was 24. In addition patients were excluded if: (i) there was a previous history of schizophrenia; (ii) in the case of RDC minor or intermittent depression, but not major depression, there was a concurrent RDC diagnosis of phobic, generalised anxiety or obsessive compulsive disorder (to rule out mild depression accompanying a predominant alternative disorder); (iii) there was a history of drug dependence, or a recent history of habitual excessive alcohol intake; (iv) there was evidence of brain damage or mental retardation (estimated IQ below 70); (v) language or other problems prevented adequate co-operation in assessment procedures; (vi) there was evidence of physical disorder precluding antidepressants; (vii) there was considered to be suicidal risk of such degree as to contraindicate placebo; (viii) the patient had in the last 3 months received a tricyclic antidepressant, or had seen a psychiatrist. Subjects gave written informed consent. Treutment Following identification by general practitioners patients were seen at home and assessed within 48 h by a research psychiatrist identified as working within the Medical School Department of General Practice. Those fitting study criteria and consenting were then started on double-blind treatment with amitriptyline or placebo using identical 25-mg tablets, according to previously prepared randomisation schedules. Patients were thereafter jointly under the treatment of the GP and the researcher. They were seen by the latter at home after 1 week, 2 weeks, 4 weeks and 6 weeks for rating and adjustment of dose, and seen by the

85 GP at intervals of his choosing, and after 6 weeks or earlier study termination. The dosages employed were in the first week three tablets (75 mg amitriptyline); in the second week four tablets (100 mg amitriptyline) reducible to three if side effects were severe; in the third to sixth week five to seven tablets daily (1255175 mg) depending on response and the research psychiatrist’s judgement, with four tablets permitted if complaints attributed by the patient to side effects were severe. Mean doses of amitriptyline in the fourth and sixth week were 119 mg, and median doses 125 mg. No other psychotropic medication was permitted except temazepam 10 mg nocte if required. Patients were withdrawn from the study if compliance was poor, minimum protocol dose was not achieved because of complaints attributed to side effects or other reasons, if co-operation was poor, or if worsening severe depression necessitated known active treatment. Considerable encouragement was given to the patient to take the prescribed dose. Compliance was monitored and found to be good. On direct questioning only 6% and 8% of patients on drug reported taking less than 75% of the prescribed dose at the fourth and sixth weeks. On returned pill count at the end of each period actual mean doses taken were 113 mg and 111 mg, approximately 95% of prescribed doses. After completion of 6 weeks or earlier dropout the code was broken independently and communicated to the GP but not to the research team. One hundred and seventy-eight patients entered the study: 141, the subjects of this report, completed a minimum of 4 weeks treatment, of whom most also completed 6 weeks. Full details of early dropouts are reported elsewhere (Hollyman et al., in press). Rating assessments At the initial pretreatment assessment, extensive data on personal, social and psychiatric history, demographic characteristics, and diagnostic classification were completed, together with an interview instrument used previously (Sireling et al., 1985a) incorporating (i) the Present State Examination (PSE) (Wing et al,, 1974); (ii) Research Diagnostic Criteria (Spitzer et al., 1978), (iii) Hamilton Rating Scale for Depression (Hamilton,

1967); (iv) Clinical Interview for Depression (Paykel, 1985) (v) Raskin Three Area Depression Scale (Raskin et al., 1970) (vi) other global ratings of depression. Self-report measures were also completed but will not be reported here. At 2 weeks, 4 weeks and 6 weeks repeated ratings were made on the Hamilton scale, Clinical Interview for Depression, Raskin scale and the global depression ratings. For the analyses to be reported here five relatively global measures of severity which had shown drug-placebo differences in the total sample were selected: (a) Hamilton Depression Scale total score (17-item version) (Hamilton, 1967) (b) Clinical Interview for Depression, total depression score (Paykel, 1985) (c) Raskin Three Area score (Raskin et al., 1970) (d) a 7-point global rating of severity of illness, (e) a 7-point global rating of change (improved a great deal, improved moderately, improved a little, no change, worsened a little, worsened moderately, worsened a great deal). Predictor variables Predictor variables were derived from the initial assessment and based on classifications which the literature suggested might be related to magnitude of drug-placebo differences. To avoid excessive searching for possibly random findings the central analyses were limited to four groups of variables: demographic, illness history, severity of illness, and classification related to endogenous or nonendogenous depression. These variables are summarised in Table 1. (a) Demographic: (i) age, (ii) sex, (iii) occupational class (Registrar General’s classification); (b) History: (i) previous episodes of depression treated by GP, psychiatrist or other treatment source, (ii) length of present illness, (iii) family history of psychiatric illness in first-degree relative, requiring GP or psychiatric treatment: (c) Seuerity of illness: (i) RDC major vs. minor and intermittent depression (this depends predominantly on the number of concomitant depressive symptoms); (ii) initial 17-item total score on Hamilton Scale; (iii) initial Three Area Raskin total; (d) Endogenous depression. The concept of endogenous depression is complex (Rosenthal and Klerman, 1966) depending on three elements which are not necessarily interrelated: symptom pattern, precipitant stress, and premorbid personality. To

86 enable each to be considered separately, several different measures were employed together with some standard measures fusing all three elements. (1) Symptom Pattern: (i) RDC endogenous depression, probable or definite. This definition only applies to major depression and minor depressives were excluded. (ii) PSE CATEGO R (retarded) vs. N (neurotic) depression. Thirty-one patients scoring below the threshold level of 5 on the Index of Definition (Wing, 1976) to whom CATEGO diagnoses cannot safely be applied, were excluded, as were six with a diagnosis of A (anxiety disorder). No patients were diagnosed as D (psychotic depression). (iii) An a priori endogenous index was constructed from symptom ratings in the Clinical Interview for Depression (Endogenous items: distinct quality, morning wakening, guilt, pessimism, impaired work and interests, anorexia, weight loss, delayed insomnia, retardation, agitation. Neurotic items: evening worsening, reactivity, depersonalisation, obsessional symptoms, psychic anxiety, panic attacks, irritability, initial insomnia, increased sleep, self-pity, overemphasis of symptoms, hysterical symptoms). (2) Stress: (i) RDC situational depression, probable or definite. This diagnosis only applies to major depressions. (ii) Rated stress at onset, using a global rating by the psychiatrist of objective negative impact of any life events and problems at onset. (iii) A clinical judgement by the psychiatrist, taking all circumstances into account, as to whether the depression was precipitated. (3) Personality: (i) Characterological depression. The psychiatrist made a global judgement of presence of preceding personality abnormality as an important element in the depression. (4) Mixed criteria: (i) Newcastle Scale (Carney et al., 1965). Because few of these mildly ill subjects satisfied the usual criterion for endogenous depression of a score of 5 or more, subjects scoring 3 or more were regarded as endogenous. (ii) Klein, for a study by Guy et al. (1983) described three types of depression. Endogenomorphic depression was characterised by a disorder with discrete onset, autonomous (non-reactive) mood and pervasive anhedonia. Disappointment reactions were characterised by a precipitant, good premorbid adjustment, and reactivity of mood. A third type, chronic dysphoria, showed a long-standing pattern of dysphoria re-

sembling RDC intermittent depression and diagnosed too infrequently in our subjects for in the analysis. Patients were assigned to the of these three types which they most closely sembled.

was use one re-

Design of analyses Outcome and predictor effects were examined by two-way analyses of covariance with initial level on the outcome measure as covariate. The global change measure was employed without covariate since there was no initial level. Analyses for all measures were confined to 6 weeks, substituting end-point rating at 4 weeks for 4-week completers. The predictor effects were examined by significance of the interaction term (drugplacebo x classification) in these analyses, indicating significantly different drug vs. placebo differences in classificatory subgroups. Significant findings were only interpreted in any subgroup analysis where at least two of the five outcome measures showed interactions significant at the 5% level,

Results

Sample characteristics The two treatment groups were well matched on initial characteristics (Hollyman et al., in press). Table 1 summarises characteristics of the two groups combined on the main predictor variables of interest in the study. The sample was varied in age, predominantly female, and working class. Almost two-thirds had a history of a previous episode of depression, mainly treated by GP: almost half had an illness less than 3 months in duration. However, there were few very short illnesses: only 14 subjects (9%) had an illness shorter than 4 weeks and another 16 (11.4%) illness of 447 weeks. Illnesses were predominantly mild, with mean Hamilton score 14.7 (67% under 16). A majority (70.9%) fitted RDC criteria for major depression, but for almost half (31.2%) this was at probable rather than definite level. The remainder were minor depressives, with only four diagnosed intermittent depressives without super-added major depression. On criteria of endogenous depression the

87 TABLE

1

PREDICTOR

CLASSIFICATIONS

USED

IN MAIN

ANALYSIS Number

Classification

Demographic Age (mean = 38.35 years) Sex Occupational class

3.4, 5

Histoty Previous depression Length of illness (median = 20 weeks) Family history of psychiatric disorder

PH positive Under 14 weeks FH positive

Over 40 Female

Severity RDC major vs. minor depression a Initial Hamilton total (mean = 14.74) Initial Raskin Three Area total (mean = 8.16) Endogenour depression Symptom pattern: RDC major endogenous b PSE/CATEGO ’ Endogenous-neurotic index Stress: RDC major situational b Rated stress at onset Judgement of precipitation Personality: Global:

a ’ ’ d

Judgement of chronic characterological depression Newcastle Scale Klein endogenomorphic d

Includes four intermittent depressives. Omits 41 minor/intermittent depressives. Omits 31 non-cases (below 5) on Index of Definition Omits 11 chronic dysphorics.

majority, varying non-endogenous.

with the criterion

employed,

Probable or definite 6-12 13-15 8 or more

major

of subjects

N

(%)

67 117 96

(47.5) (83.0) (68.6)

90 61 71

(63.8) (43.3) (56.0)

100 40 47 94

(70.9) (28.4) (33.3) (66.7)

Probable or definite endogenous Retarded (R + ) Endogenous Not situational None or mild negative impact Definitely or probably not precipitated

30 50 53 34 37

(21.3) (35.5) (37.6) (24.1) (26.2)

26

(18.4)

Not characterological 3 or more Endogenomorphic

59 54 56

(41.8) (38.3) (39.7)

and six A (anxiety)

were

Main effects for treatment Fig. 1 shows mean scores for the five outcome measures over time in the two treatment groups, without separation by classificatory subgroup. Superiority of amitriptyline over placebo was present by 2 weeks, and was strong and significant on all measures by the end of the study. These general findings, on a larger pool of outcome measures, are reported fully elsewhere (Hollyman et al., in press). Detailed analysis of symptom ratings confirmed a true antidepressant effect on core symptoms of depression.

diagnoses

Summary of interactions Table 2 summarises findings of the interaction analyses by indicating for each classification the number of outcome measures out of the five analysed showing significant interactions at the 5% level or better. Interactions with drug response were virtually absent for demographic and history variables, and for the various classifications reflecting different aspects of endogenous depression. The general finding was one of strong drug-placebo differences, extending across most subgroups. Only in respect of two classifications reflecting initial severity did interactions reach the criterion taken of two variables achieving 5% significance: for RDC major vs. minor depression,

HAMILTON

TOTAL M

CLINICAL

INTERVIEW

amitriptyline

m+-- placebo

2

WEEKS

4

0

2

THREE

TOTAL

M

amitriptyline

c+-<:

placebo

4

WEEKS

GLOBAL RASKIN

DEPRESSION

6

ILLNESS

AREA

M

amitriptyline

+--:

placebo

11

M

amitriptyline

-+-o

placebo

’

I

1

I

0

2

4

6

WEEKS

WEEKS

GLOBAL

CHANGE -

amitriptyline --4

WEEKS

placebo

Fig. 1. Mean scores on maln outcome

measures

over 6 weeks.

89 TABLE

2

NUMBER OF PREDICTOR TERACTIONS SIGNIFICANT

ANALYSES SHOWING AT 5% LEVEL

Demographic

class

Table 3 shows adjusted final means and significances of main effects and interactions from the analyses for the classifications of RDC major vs. minor depression (the latter included four intermittent depressives). Main effects for drug-

1 _ _

disorder

Severity RDC major vs minor depression Initial Hamilton total Initial Raskin 3 Area total

RDC

MAJOR

AND

MINOR

2 2 0

Endogenous depression Symptom pattern: RDC major endogenous PSE/CATEGO Endogenous-neurotic index RDC major situational Stress: Rated stress at onset Judgement of precipitation Judgement of chronic Personality: characterological depression Newcastle Scale Global: Klein endogenomorphic

DEPRESSION

-

amitriptyline

~+-a

placebo

_ _ I

_ _

1

0 Fig. 2. RDC

-

WEEKS

6

major and minor depression. Initial Hamilton scores in treatment groups.

and

3

ANALYSES Outcome

Major and minor depression

_ _ _

History Previous depression Length of illness Family history of psychiatric

TABLE

IN-

Number of analyses showing significant interactions

Classification

Age Sex Occupational

and initial Hamilton Scale score. Even for each of these significance was reached in only two of the five analyses although most of the other outcome measures showed similar trends reaching the 10% level of significance.

OF COVARIANCE:

measure

Adjusted

RDC MAJOR

Amitriptyline (n = 45)

a Unadjusted

DEPRESSION Significance

mean final score Minor depression

Major depression

Hamilton total Clinical Interview Depression total Raskin Three Area scale Global severity of illness Global change a

VS. MINOR

Placebo (n = 55)

Amitriptyline (n =19)

Main effects Placebo (n =18)

Interaction

Drugs vs. placebo

Major vs. minor

drug X classification

4.74

9.13

6.86

7.29

< 0.05

NS

i 0.05

13.03

16.69

14.91

15.26

< 0.05

NS

NS

4.86

6.16

5.36

5.47

< 0.05

NS

NS

1.90 1.78

2.75 2.69

2.21 1.79

2.24 2.00

< 0.05 < 0.05

NS NS

i 0.05 NS

score, no covariate.

final

90 placebo differences were significant on all outcome measures. There were no main effects for the classification, indicating that overall, after adjustment of final score for the correlation with initial level of illness, major and minor depressives did not differ in outcome. There were significant interactions at the 5% level on two outcome measures: Hamilton total and global severity of illness: a third, the Raskin Three Area total, reached the 10% trend level. All outcome measures showed the same consistent pattern. This is best seen Fig. 2, which shows unadjusted mean scores on the Hamilton Scale at initial rating and at the end of the study, with intermediate points omitted for clarity. For minor depressives, initially less severe, drug and placebo groups both improved but remained closely similar. For major depressives, starting more severe, the amitriptyline group improved considerably more than the placebo group, to reach similar levels at the end of the study to the minor depressives. Active drug was beneficial to major depressives but not to minor.

Initial Hamilton score Table 4 shows similar data for the three groups based on initial level of the Hamilton total score:

TABLE

HAMILTON

1 0

SCORE

-

amitriptyline

s--i:

placebo

I WEEKS

6

Fig. 3. Subgroups based on initial Hamilton scores. Initial final scores in treatment groups.

OF COVARIANCE:

measure

INITIAL

TOTAL

Adjusted

mean final scores

Hamilton

6-12

Amitriptyline (n = 20)

Placebo (n = 20)

Hamilton Amitriptyline (n = 20)

HAMILTON

SCORE Significance

13-15 Placebo (n = 27)

Hamilton Amitriptyline (n = 27)

16-24 Placebo (n = 27)

Main effect Drug vs. placebo

Initial Hamilton

Interaction drug x initial Hamilton

Hamilton 7.49

7.01

5.47

9.20

3.94

9.25

i 0.01

NS

i 0.05

total Raskin Three

14.71

14.09

13.77

17.33

12.61

16.79

< 0.01

NS

NS

Area scale Global severity

4.94

4.89

4.96

6.03

5.08

6.67

i 0.01

NS

NS

2.21 1.85

2.09 1.80

1.80 1.70

2.73 2.78

2.02 1.81

2.84 2.74

< 0.01 < 0.01

NS NS

i 0.05 NS

total Clinical Interview Depression

of illness Global change a Unadjusted

a

score, no covariate.

and

6-12, 13-15, 16-24. As would be expected, main drug effects were again significant on all variables. Again there were no main effects for the classification, indicating no consistent differences independent of treatment group in outcome, after adjustment for initial level. There were significant interactions on two outcome measures, Hamilton total

4

ANALYSES Outcome

INITIAL

91 and global severity of illness; all three remaining outcome measures reached 10% trend significance. Fig. 3 illustrates findings as before, using unadjusted mean scores on the Hamilton total. There was a very similar pattern to that for major and minor depression. Here however it was only the very mildly ill patients with initial Hamilton scores of 6-12 who showed no benefit from active drug. There were considerable drug-placebo differences for the two other patient groups, and again the effect was to produce final scores on amitriptyline close to those of the mildly ill. RDC classification and severity In order to confirm the relationship between the two preceding sets of analyses, groups selected on the basis of major vs. minor depression and initial Hamilton score were cross-tabulated. Findings are shown in Table 5. The two classifications were associated at a high level of significance. Two-thirds of minor depressives had Hamilton total scores below 13. Additional exploratory analyses Following the main analyses an additional exploratory set was carried out to examine whether dividing the sample by initial score or any individual symptom ratings would produce interactions with treatment outcome. The analyses were particularly concerned with so-called biological symptoms of depression, with reversed functional shift and anxiety. The following ratings from the Clinical Interview for Depression were used for this purpose, each giving rise to a set of analyses on

TABLE

5

RELATIONSHIP AND HAMILTON Hamilton total

6-12 13-15 16-24

BETWEEN SCORE

RDC

CLASSIFICATION

RDC classification Minor n

Major n 13 34 53

21 13 1

100

41

a Includes four intermittent x2 = 48.1, P < 0.001.

depressives.

a

the same five outcome measures as used previreactivity, guilt, anorexia, weight loss, ously: suicidal tendencies, any diurnal variation (morning worsening and evening worsening combined), initial insomnia, psychic anxiety, phobic anxiety. Additional ratings of loss of interest and loss of pleasure were also used in the same way. A number of further symptoms were rated as present too infrequently for use in this way (under 40 subjects in total or 15 in one treatment group rated as at least mild): morning worsening, evening worsening, retardation, delayed insomnia, increased sleep, increased appetite, weight gain. Since these analyses were guided to some extent by the findings in the main set, and since they considerably increased the total set of analyses, it was accepted that any significant findings would require cautious interpretation. In fact, however, no set reached the criterion of two interactions in the five analyses of outcome measures reaching 5% significance. Evidently only the element in individual symptom ratings reflecting general severity, when combined to a total or global measure, influenced treatment effects. Discussion Previous studies Earlier views that tricyclic antidepressants were specifically effective in endogenous depressives and the severely ill have needed modification in recent years. A critical look at the earlier controlled trials suggests that, although the effect may have been a little better in endogenous depressives, there was evidence of benefit in neurotic depressives (Paykel, 1979). Many controlled trials have shown tricyclics superior to placebo in outpatient depressives (Morris and Beck, 1974) and in samples characterised as neurotic or reactive (Ball and Kiloh, 1959; Wittenborn et al., 1962; Uhlenhuth and Park, 1964; Covi et al., 1974; Friedman, 1975). So-called neurotic depressives are themselves heterogeneous (Paykel, 1971; Klerman et al., 1979). Differences in drug response and spontaneous course are not well studied. In outpatients Prusoff et al. (1980) found better response to amitriptyline in depressions with endogenous symptom pattern, and to psychotherapy in situational depressions

92 (the two were not mutually exclusive). On the other hand, using extensive alternative classifications, Paykel et al. (1982) found amitriptyline clearly superior to placebo in a wide range of outpatient depressives and anxiety depressives. It has been suggested that monoamine oxidase inhibitors are preferentially effective in depressives with anxiety or reversed functional shift (such as increased appetite, increased sleep or initial insomnia, evening worsening) (Tyrer, 1976; Liebowitz et al., 1984). However, in the study cited above (Paykel et al., 1982) we found no evidence of differences based on reversed functional shift and phenelzine was only weakly superior to amitriptyline where anxiety was present. There is increasing evidence that tricyclics are superior to placebo in agoraphobics (Sheehan et al., 1980; Zitrin et al., 1980; Marks, 1983). In two large studies comparing &cyclic antidepressant, benzodiazepine and placebo in a spectrum of anxious and depressed patients, the tricyclic was consistently superior to placebo while the benzodiazepine showed only weak effects (Johnstone et al., 1980; Kahn et al., 1986). More recent findings regarding deluded depressives also contradict earlier views. Although delusions are associated with psychotic/endogenous depression, there have been a number of reports indicating that they predict a poor response to tricyclic antidepressants and a good response to electroconvulsive therapy (Paykel, 1979). The best response to tricyclics may be shown by patients in an intermediate range of endogenous symptoms (Rao and Coppen, 1978). It is particularly at the milder end of the spectrum that good evidence is lacking. It has usually been assumed that mild depression near the normal range has a good spontaneous outcome and is not improved by antidepressants. However, DiMascio et al. (1968) found imipramine superior to placebo in a group of normal volunteers who scored relatively high on a depression self-report scale: those who scored low showed no such effect. Two recent American trials bear on this question. Guy et al. (1983) treated RDC major, minor or intermittent depressives not scoring above 18 on the Hamilton Scale with mianserin or placebo for 6 weeks, Using Klein’s typology the drug was

superior to placebo in endogenomorphic depressives and chronic dysphorics, but not in disappointment reactions. In a study more directly comparable with our own, Stewart et al. (1983) treated 64 depressives fulfilling similar criteria to those of Guy et al. with desipramine or placebo. There were few minor depressives. The drug was superior to placebo in major but not intermittent depression; although numbers were somewhat low there was no convincing evidence of better response in any subtype of major depression. Patients with initial Hamilton scores of 14-18 showed drug superior to placebo, those with Hamilton scores of 13 or under did not. Later analyses (Stewart et al., 1985) confirmed that the antidepressant was superior to placebo in DSM-III major depression, both without and with melancholia, but not in dysthymic disorder. It also appeared effective in patients with panic attacks. Present findings The study found strong drug-placebo differences. Overall these were more impressive than any predictor effects; there were relatively few subgroups which did not show drug superior to placebo and only some outcome measures showed significant interactions. However, these fell into a consistent pattern. It should also be noted that the method of analysis was a conservative one. For a significant interaction effect to appear the difference in magnitude of drug-placebo differences must be considerable: the method is most powerful where differences go in opposite directions in subgroups. We had no hypotheses that any subgroup would improve less on drug than on placebo; merely, that active drug would confer no further benefit. The findings indicate that amitriptyline is beneficial therapeutically in all but the most mild depressives. For depression above this range the effect of antidepressants was to reduce the level of symptoms after 6 weeks to that reached on placebo by the most mildly ill. There appeared to be a level which very mild patients reach spontaneously, which represents improvement rather than no change, and is as much as can be achieved in 6 weeks: the effect of active drug is to move the patients in the higher ranges of what is still relatively mild disorder down to this floor.

93 The threshold at which this effect started was a relatively low one: a Hamilton score of 13 represents mild depression, well below the minimum level of 17 usually applied in outpatient antidepressant trials. The whole sample was relatively mildly ill. The analysis in Table 5 confirmed that the division into major and minor depressives, which depends on number of symptoms, was related to severity on the Hamilton Scale. Separate analyses not shown in the Tables indicated that the drug-placebo difference was as great in those who only reached the threshold for probable (mean initial Hamilton score 14.3), rather than definite, major depression (mean initial Hamilton score 17.5). Over one-third of minor depressives were found to be above this threshold of 13 (Table 5). The results showed considerable consistency with those found by Stewart et al. (1983, 1985) in a psychiatrically treated sample, but one particularly selected for mild illness, in an American setting where psychiatrists act more commonly as first contact treatment providers for depression. Age, sex and social class failed to distinguish those benefitting from antidepressant. Overall the literature does not suggest strong effects for these variables. Neither were there effects for history of previous depression or length of illness. It might have been expected that transient depression would have good prognosis and fail to show benefit from drugs. However, there were few very short-lived depressions in the sample, possibly because patients do not consult GPs, tend not to be recognised, and are not regarded as suitable for antidepressant treatment, until some time has elapsed. There was a trend, reaching significance on only a single outcome measure, for greater drug-placebo differences in subjects with a previous history of depression, suggesting a greater value for treatment in a recurrent rather than single episode disorder. More surprising in the light of early studies, although quite consistent with the findings in the Stewart study and our own earlier outpatient study (Paykel et al., 1982), was the absence of any differentiation by the presence of endogenous or non-endogenous depression. The concept of endogenous depression is complex and we therefore used a number of alternative measures. Recent studies (Paykel, 1982) indicate that there is only a

weak correlation between absence of stress and presence of endogenous symptoms. Most predictor studies in the literature and most recent definitions lay more emphasis on symptom patterns. In the mild range of depression, it would not appear that absence of either feature points to absence of antidepressant benefit. Likewise individual biological symptoms, reversed functional shift disturbances or anxiety symptoms carried no implications for therapeutic response. Some selection is inevitably involved in the patient career path of subjects into drug trials. We were fortunate that data were available from a previous survey study (Sireling et al., 1985a,b) planned as a preliminary to this one. In that study, about half of a representative sample of patients started by GPs on a new course of antidepressants were RDC major depressives, a quarter minor or intermittent depressives and the remainder received other RDC diagnoses, although some depressive symptoms were present. In the present study, the 25% with other diagnoses were excluded, since they were only doubtfully appropriate to an antidepressant trial. Analyses were carried out to compare the present subjects with the RDC depressives from the earlier study and are reported elsewhere (Hollyman et al., in press). Amongst a large set of variables examined, few showed differences. The results appear reasonably generalisable, except that no conclusions can be drawn regarding subjects who do not qualify for a depressive diagnosis, and minor depressives with anxiety diagnoses who were excluded by the criteria. Intermittent depressives (DSM-III dysthymic disorder) were infrequent both in this study and in the earlier survey study, and do not appear commonly to be treated by GPs with new courses of antidepressants. Also, in this study considerable effort was devoted to achieving adequate dosage and compliance. This does not apply in routine treatment, but the findings would argue to its value. The study design did not include comparison with other active treatments. There is evidence from general practice controlled studies in Britain that cognitive therapy is as effective as tricyclic antidepressant (Blackburn et al., 1981) or GPs’ usual treatment (Teasdale et al., 1984). Other controlled studies in psychiatric outpatient clinics in-

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